Over the last several years, by use of a pancreatic beta cell subtraction library, we have succeeded in isolating five novel genes. During the past 12 months the emphasis has been on human IA-2-beta which we sequenced and expressed. IA-2-beta is a member of the protein tyrosine phosphatase family and structurally similar to IA-2 with an extracellular, transmembrane and intracellular domain. Despite the structural similarity, the sequence of IA-2 and IA-2-beta are quite different: the intracellular domain of IA-2 is 74% identical to IA-2, whereas the extracellular domain of IA-2-beta is only 26% identical to IA-2. IA-2 mRNA is found primarily in pancreatic islets and brain. Approximately 40% of IDDM sera react with IA-2-beta whereas close to 70% of IDDM sera recognize IA-2. Autoantibodies to IA-2 and/or IA-2-beta appear years before the development of clinically apparent IDDM and are, therefore, highly predictive markers for identifying individuals likely to develop clinical disease. Ongoing studies indicate that the presence of autoantibodies to more than just one islet cell autoantigens (e.g., IA- 2/IA-2-beta and glutamic acid decarboxylase) is even more highly predictive than autoantibodies to any single autoantigen.